The present invention relates to pharmaceutical compositions for delivering drugs.
Liposomes and hyaluronic acid have each been used as drug carriers in topical drug delivery systems.
For a review of literature on the use of liposomes as dermal drug delivery vehicles see Gary P. Martin “Phospholipids as Skin Penetration Enhancers ” King's College University of London, London, United Kingdom, pp. 57-84, 1993.
Liposomes are vesicles in which an aqueous compartment or volume is entirely enclosed by a membrane of lipid molecules which are usually phospholipids. Liposomes may be formed spontaneously when lipids are dispersed in aqueous media, producing a population of liposome vesicles having average maximum diameters ranging from nanometers to microns. Liposomes can be formed such that they will entrap molecules within one or both of the aqueous compartment and the membrane. In fact, liposomes can be formed from natural constituents such that their membrane or membranes forms or form a bi-layer which is similar to the lipid arrangement in natural cell membranes. It is possible that this similarity can be exploited in drug targeting or immune modulation, both in vitro and in vivo, where the liposome's ability to mimic the behavior of natural membranes and, therefore, to be degraded by the same pathways, make liposomes an extremely safe and efficacious drug vehicle for medical use.
Apart from the chemical constituents of liposomes which determine their fluidity, charge density, and permeability, liposomes can be characterized by size and shape. Liposomes have average maximum diameters ranging from 25 nanometers to greater than 1,000 nanometers, which coincide with the average maximum diameters of living cells. As indicated above, liposomes may include a single bi-layer membrane. However, they may also include multiple concentric membrane lamella successively surrounding one another. It is possible, therefore, to group liposomes into one of the following categories based on the number of layers of membranes and relative average diameters: multilamellar vesicle (MLV) liposomes, small unilamellar vesicle (SUV) liposomes, large unilamellar vesicle (LUV) liposomes, and intermediate-sized unilamellar vesicle (IUV) liposomes. See New, R. C, “Liposomes—A Practical Approach,” Oxford University Press, Oxford, pp. 1-33, 1990.
Several factors such as lamellarity (that is, the number of lamella), lipid composition, charge on the liposomal surface, and the total lipid concentration have been proven to influence drug deposition within the deeper skin strata. See, for example, Weiner et al. “Topical Delivery of Liposomally Encapsulated Interferon in a Herpes Guinea Pig Model,” Antimicrob. Agents Chemother., 33: 1217-1221, 1989. There has also been much discussion on the mechanism of liposome diffusion in skin. Originally, it was thought that liposomes diffused intact through to the dermis where they became localized as set forth in Mezei, M. and Gulasekharam, V., “Liposomes—A Selective Drug Delivery System for the Topical Route of Administration,” Life Sci., 26: 1473-1477, 1980. Later, this theory was criticized by Ganesan et al. “Influence of Liposomal Drug Entrapment on Percutaneous Absorption,” Int. J. Pharm., 20: 139-154, 1984; and Ho et al. “Mechanism of Topical Delivery of Liposomally Entrapped Drugs,” J. Controlled Rel., 2: 61-65, 1985, as it was thought that the densely packed stratum corneum would not allow the passage of liposomes through to the epidermis and dermis. Egbaria, K. and Weiner, N., “Topical Application of Liposomal Preparations,” Cosmet. Toilet., 106: 79-93, 1991, postulated that molecular mixing of the bi-layers of the liposome and the stratum corneum takes place. There have also been indications that the follicular pathway contributes to the liposomal delivery of drugs into the skin as discussed in Du Plessis et al. “Topical Delivery of Liposomally Encapsulated Gamma-Interferon,” Antiviral Res., 18: 259-265, 1992; and evidence that the size of the liposome is important as described in Du Plessis et al. “The Influence of Particle Size of Liposomes on the Deposition of Drug into Skin,” 103: 277-282, 1994.
Liposomes have been used also for non-topical or parenteral drug delivery. For evaluation of the effectiveness of liposomal drug delivery, researchers have determined (1) the effect of components of biological fluids on the structural integrity of liposomes and (2) the rates at which liposomes are cleared from the administration site and distributed into the tissues. With both parameters, the behavior of liposomes is dictated by their structural attributes. Specifically, as the stability of the liposomes increases their rate of clearance from the site of administration decreases. Their circulation times, however, can be controlled by using smaller liposomes, altering their lipid composition or rendering the liposomes hydrophilic. Gregoriadis, G., “Liposomes in Drug Delivery: Present and Future,” 346-352.
Notwithstanding this extensive knowledge and literature, liposomes alone are sometimes deficient as drug delivery vehicles due to their instability and/or their unsatisfactory penetration characteristics in particular systems.
As discussed and claimed in PCT Publication No. 93/16732, hyaluronic acid has also been known as a vehicle for topical delivery of pharmaceutical agents. Hyaluronic acid is extremely hydrophilic, however, and thus, has not been successfully combined with hydrophobic drugs such as cyclosporin A.
It has been discovered that there are many proteins which bind HA, including several different cell receptors having a variety of functions, including receptors related to tumor cells. Thus, it has been suggested that based on the variety of modes by which HA can interact with cells it must have several regulatory functions.
Many drugs, one example of which is cyclosporin A (molecular formula C62H111N11O62; sometimes referred to hereafter as CsA), are difficult to administer. Cyclosporin A is a cyclic undecapeptide antibiotic produced by the fungus Tolypocladium Inflatum and is highly lipophilic. Cyclosporin A is also virtually insoluble in water and hydrophobic, as indicated above. Cyclosporin A is a potent T-lymphocyte cell-specific immunosuppressant which is primarily used for prophylaxis and treatment of organ rejection in renal, hepatic, cardiac, and pancreatic transplantation. It has also been administered orally or intramuscularly in the treatment of psoriasis as discussed in Ellis et al. “Cyclosporin Improves Psoriasis in a Double Blind Study,” JAMA, 256:3110-3116; Griffiths et al. (1987) “Cyclosporine and Psoriasis,” Lancet, i: 806, 1986.
When administered orally, cyclosporin A is usually administered as an olive oil based micro emulsion solution mixed with beverages. Cyclosporin A may also be administered as an intravenous injection. The drug is solubilized using the solubilizing agent Chremophor EL, a mixture of olive oil and polyethoxylated castor oil (also known by the tradename Neoral). Systemic administration of such a cyclosporin A formulation, however, leads to several side effects such as anaphylactic reactions, adult respiratory distress syndrome, nephrotoxicity, gastrointestinal problems, hepatoxicity, angioedema, and mild tremor as reported in Thomson, A. W., “Immunobiology of Cyclosporin: A Review,” Aust. J. Exp. Biol. Med. Sci., 61: 147-172, 1983. It is believed that a number of these adverse reactions are caused by the drug vehicle itself as discussed in Williams et al. “Intravenous Cyclosporin and Kidney Function: The Johns Hopkins Experience,” Transplant. Proc., 18: 66-73, 1986; and Luke et al. “Effects of Cyclosporin on the Isolated Perfused Rat Kidney,” Transplantation, 43: 795-799, 1987.
The incidence of systemic side effects may be markedly reduced by delivering cyclosporin A topically, although previous studies involving transdermal delivery of cyclosporin A for the treatment of psoriasis using oil in water emulsions have proven this delivery method to be ineffective. See, for example, Gilhar et al. “Topical Cyclosporin in Psoriasis,” J. Am. Acad. Dermatol., 18: 378-379, 1988; and Hermann et al. “Topical Cyclosporin for Psoriasis,” Skin Pharmacol., 1: 246-249, 1988. In addition, the side effects may be reduced by using a less antagonistic carrier. Thus, there is a need for a non-toxic dosage form of cyclosporin A and a safe route of administration.
A combination of CsA and liposomes is not satisfactory because of the physical instability of the combination. That is, liposomes in the liposome/CsA combination may break down causing the CsA to separate from the liposomes or the CsA may separate from the liposomes even where the liposomes do not break down. A suitable combination had yet to be developed. Hyaluronic acid, alone, also fails as a carrier for CsA because of the lipophilic, hydrophobic nature of CsA.
HA and liposomes, individually, fail also to be good carriers for other drugs which are lipophilic and hydrophobic.